Mantle cell lymphomas (MCLs) are deadly lymphoid malignancies that arise from presumptive B cells of origin. Prior studies of MCL and other lymphomas revealed the presence of tumor cells with stem-like characteristics, although the exact identities and molecular properties of these cell types have remained obscure for decades. Our group has used monoclonal antibodies directed against B cell surface proteins, freshly isolated patient samples, and limiting dilution assays in mice to prospectively isolate and characterize stem-like tumor cells from multiple MCL. Gene expression profiling analyses of MCL initiating cells (MCL-ICs) revealed that MCL- ICs up-regulate NF-kB related signaling components and CXCR4-mediated mobilization pathways compared to the bulk tumor cells. In this proposal we will investigate how these molecular pathways are interconnected to confer growth, survival and drug resistant properties to MCL-ICs. In Aim1 we will delineate molecular mechanisms of MCL drug resistance and link these features to stem-like functions. We hypothesize that stem-like MCL cells utilize TG2 and NF-kB signaling to compensate for diminished B cell receptor-mediated growth and survival due to lack of CD19 expression, as has been reported in Hodgkin's Lymphomas. In Aim2 we will target drug resistant MCL cells by inhibiting autophagy. We discovered that bortezomib treatment induces autophagy in MCL cells, contributing to survival of the MCL cells. In addition, TG2/NF-kB pathway is reported to play important functions for autophagy. We hypothesize that bortezomib resistant MCL cells utilize autophagy as an alternative route for IkBa degradation, which in turn enhances their survival via NF-kB activation. In Aim3 we will enhance bortezomib sensitivity of MCL cells by inhibiting their mobilization to the bone marrow. We have demonstrated that MCL-ICs migrate in response to CXCL12 which is expressed in the bone marrow microenvironment, and neutralizing antibodies directed against the major receptor for CXCL12, CXCR4, inhibit their mobilization. We hypothesize that the CXCR4 signaling on MCL cells mediates interactions with bone marrow stromal cells and that disrupting these interactions will sensitize MCL cells to bortezomib. Given that malignant stem cells in some cancers are highly drug resistant and give rise to new tumors after drug therapies, targeting the pathways selectively expressed in stem cells in MCL may ultimately improve survival of MCL patients.